1. Field of the Invention
The present invention relates to the field of metabolic compound conjugates and variant metabolic compounds, and uses of these in the treatment of diabetes and conditions related to this condition.
2. Description of Related Art
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems: cells may be starved for energy and high blood glucose levels may damage eyes, kidneys, nerves or heart.
Currently in the United States, 13 million individuals have a diagnosis of diabetes, an estimated 5 million more are suffering from undiagnosed diabetes, and the numbers continue to grow. Approximately 10% of those afflicted have type 1 diabetes, while the rest have type 2. The morbidity and mortality associated with diabetes are related to the short- and long-term complications. Complications include hypoglycemia and hyperglycemia, increased risk of infections, microvascular complications (e.g., retinopathy, nephropathy), neuropathic complications, and macrovascular disease. Diabetes is the major cause of blindness in adults aged 20-74 years, as well as the leading cause of nontraumatic lower-extremity amputation and end-stage renal disease (ESRD).
The first treatment for type 2 diabetes is often meal planning for blood glucose (sugar) control, weight loss, and exercising. Sometimes these measures are not enough to bring blood glucose levels down near the normal range. The next step is taking a medicine that lowers blood glucose levels. In individuals with diabetes, blood glucose levels are too high. These high levels occur because glucose remains in the blood rather than entering cells, where it is utilized. But for glucose to pass into a cell insulin must be present and the cell must be “hungry” for glucose. Individuals with type 1 diabetes don't make insulin. For them, insulin shots are the only way to keep blood glucose levels down. Individuals with type 2 diabetes tend to have two problems: they don't make quite enough insulin and the cells of their bodies don't seem to take in glucose as eagerly as they should.
Metabolic peptides have been used in the treatment of many diseases. For example, glucagon-like peptide (GLP-1) was first identified in the early 1980's and exists in two major forms, GLP-1 (7-36) amide (FIG. 1) and GLP-1 (7-37) (FIG. 2). Both peptides have been shown to be equipotent, but the main peptide in circulation is the GLP-1 (7-36) amide. GLP-1 is processed from the proglucagon gene in the L-cells of the small intestines and has several therapeutic properties. The most desirable antidiabetic action of GLP-1 is its glucose dependent secretion of insulin. Upon the intake of nutrients, GLP-1 is stimulated by the increase in plasma glucose levels and acts at the pancreas to stimulate the production of insulin. Thus, GLP-1 is glucose dependent and only stimulates insulin release as long as there is enough glucose to warrant it. By contrast, most conventional treatments for type 2 diabetes involve insulin secretion that is glucose independent. The properties of GLP-1 make it a suitable candidate for the treatment of non-insulin-dependent diabetes mellitus and type 2 diabetes.
The limitation of GLP-1 as a therapeutic treatment is due to its short in vivo half life (<2 minutes). GLP-1 is degraded rapidly by dipeptidyl peptidase IV (DPP-IV) which cleaves GLP-1 between the 8-9 positions and renders it biologically inactive. In order for GLP-1 to be an effective therapeutic agent, the in vivo half life must be extended and GLP-1 protected from DPP-IV degradation.
A peptide resembling GLP-1 known as exendin-4 is found in the saliva of the Gila monster, a poisonous lizard that lives in the Southwestern United States. The Gila monster eats large, but infrequent, meals. These lizards eat as few as four times each year, storing large amounts of fat in their tails. When the lizard eats, the exendin-4 in the spit of the animal “wakes” the pancreatic islet cells, resulting in beta-cell activity, insulin release, and control of glucose and fat metabolism.
Although exendin-4 was originally found to stimulate amylase secretion from pancreatic acinar cells, subsequent experiments demonstrated that exendin-4 was a potent agonist for the mammalian GLP-1 receptor, consistent with the ˜53% amino acid identity that exendin-4 shares with GLP-1. The available evidence suggests that exendin-4 exerts the majority of its glucose-lowering effects through the GLP-1 receptor. Exendin-4 displays similar functional properties to native GLP-1, and regulates gastric emptying, insulin secretion, food intake, and glucagon secretion. Exendin-4 lowers blood glucose in normal rodents and in both mice and rats with experimental diabetes, as reviewed in regulatory peptides (Barragan, Rodriguez et al. 1996).
Exenatide is a synthetic version of exendin-4. It is DPP-IV resistant and has many of the actions of GLP-1. That is, it slows stomach emptying, increases satiety and decreases food intake, and leads to increased release and synthesis of insulin. Exenatide was approved by the FDA in April 2005 for treatment of type 2 diabetes.
Notably, there are practical limitations that exist in using peptides as drugs. Proteolysis, both in the gut and in the bloodstream, is a major barrier to using peptides as therapeutics. Another difficulty encountered with non-endogenous peptides is immunogenicity. The peptides that have been used as therapeutics have generally been limited to administration by repeated subcutaneous injections or by continuous intravenous infusion. As a result of these problems, the approach of the pharmaceutical industry has been to create small, non-peptide molecules using medicinal chemistry. While this approach has met with some success, it is costly, time consuming, and fraught with uncertainty in terms of pharmacokinetics and toxicity. Furthermore, identification of small organic molecules with agonist activity at peptide receptors has proved exceptionally challenging.
Thus is would be advantageous to provide for peptidic conjugate drugs that may be administered and preferably orally administered that exhibit reduce immunogenicity while increasing effectiveness and bioavailability.